A mouse herpesvirus induces relapse of experimental autoimmune arthritis by infection of the inflammatory target tissue

It is not known what is required for successive relapses in autoimmune diseases or evolution to a progressive chronic disease. Autoimmune arthritis caused by passive transfer of autoantibodies against glucose 6-phosphate isomerase is transient and therefore lends itself well to test for what might extend the disease. Herpesviruses have long been suspected of contributing to human autoimmune disease. We infected mice with a murine gamma-herpesvirus (MHV-68). In immunodeficient mice, transient arthritis was followed by a relapse. This was due to lytic viral infection of synovial tissues demonstrated by PCR, immunohistochemistry, and electron microscopy. Latent infection could be reactivated in the synovium of normal mice when treated with Cytoxan and this was associated with increased clinical arthritis. We conclude that herpesviruses may play an ancillary pathogenic role in autoimmune arthritis by infection of the inflammatory target tissue.     

Allergic Complications of Meningococcal Disease I—Clinical Aspects

Out of 717 patients with meningococcal disease 53 showed one or more of the three allergic complications: 47 (6·6%) developed arthritis, 12 (1·7%) developed cutaneous vasculitis, and 6 developed episcleritis. These complications, which were often multiple, occurred six to nine days after the beginning of the illness and three to six days after the start of successful antibiotic therapy. Those patients with severe systemic disease were prone to the complications.Histological and bacteriological study of the arthritis and vasculitis showed that these lesions were probably not due to persisting infection and suggested that they might be due to immune complex disease.     

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

Pathologies caused by mutations in extracellular matrix proteins are generally considered to result from the synthesis of extracellular matrices that are defective. Mutations in type X collagen cause metaphyseal chondrodysplasia type Schmid (MCDS), a disorder characterised by dwarfism and an expanded growth plate hypertrophic zone. We generated a knock-in mouse model of an MCDS–causing mutation (COL10A1 p.Asn617Lys) to investigate pathogenic mechanisms linking genotype and phenotype. Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone. Chondrocytes in the hypertrophic zone exhibited endoplasmic reticulum (ER) stress and a robust unfolded protein response (UPR) due to intracellular retention of mutant protein. Hypertrophic chondrocyte differentiation and osteoclast recruitment were significantly reduced indicating that the hypertrophic zone was expanded due to a decreased rate of VEGF–mediated vascular invasion of the growth plate. To test directly the role of ER stress and UPR in generating the MCDS phenotype, we produced transgenic mouse lines that used the collagen X promoter to drive expression of an ER stress–inducing protein (the cog mutant of thyroglobulin) in hypertrophic chondrocytes. The hypertrophic chondrocytes in this mouse exhibited ER stress with a characteristic UPR response. In addition, the hypertrophic zone was expanded, gene expression patterns were disrupted, osteoclast recruitment to the vascular invasion front was reduced, and long bone growth decreased. Our data demonstrate that triggering ER stress per se in hypertrophic chondrocytes is sufficient to induce the essential features of the cartilage pathology associated with MCDS and confirm that ER stress is a central pathogenic factor in the disease mechanism. These findings support the contention that ER stress may play a direct role in the pathogenesis of many connective tissue disorders associated with the expression of mutant extracellular matrix proteins.     

Klebsiella pneumoniae glycoprotein RU-41740 enhances resistance of mice against Mycoplasma arthritidis-induced arthritis

The effect of a purified glycoprotein extract from Klebsiella pneumoniae with non-specific immunostimulating properties (RU 41740) on the development and course of mycoplasma arthritis was investigated. Male A/J mice aged 2-3 months were given RU-41740 either intraperitoneally (i.p.) or orally prior to injection with Mycoplasma arthritidis. RU-41740 injected i.p. at 0.1 mg kg-1 or given orally at 1 mg kg-1 prior to the infection and subsequently on alternate days enhanced the resistance of mice to mycoplasma arthritis (P less than 0.001). Doses of 1 mg kg-1 i.p. or 10 mg kg-1 orally did not modify the course of the arthritis significantly, probably due to immunosuppressive factors from monocytes. It is suggested that RU-41740 protects the mice by stimulating macrophages. This immunostimulant might prove useful in the treatment of mycoplasma diseases, especially in the immunocompromised host.     

Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators

Various experimental and epidemiological studies have demonstrated that helminth infections affect outcomes of allergic or autoimmune disorders. Here, we examined the effects of Schistosoma mansoni infection on mouse collagen-induced arthritis, one of the most widely used animal models for rheumatoid arthritis. Male DBA/1 mice were infected with S. mansoni 2 weeks prior to being immunized with type II collagen (IIC). Cytokine mRNA expression in mouse paws, cytokine production by ConA-stimulated spleen cells, and anti-IIC antibodies were evaluated in addition to the severity of arthritis. S. mansoni infection significantly reduced the severity of arthritis. Anti-IIC IgG and IgG2a levels were lower in infected than uninfected mice. With regard to cytokine producing potentials in the infected mice, the down-regulation of Th1 (IFNγ) and pro-inflammatory cytokines (TNFα and IL-17A), and up-regulation of Th2 (IL-4) and an anti-inflammatory cytokine (IL-10) were observed. In addition, real-time PCR revealed that the augmentation of pro-inflammatory mediators such as IL-1β, IL-6 and receptor activator of NFκB in inflamed paws was abrogated by S. mansoni infection. In conclusion, schistosome infection reduced the severity of autoimmune arthritis via systemic and local suppression of pro-inflammatory mediators, suggesting the potential of parasite-derived materials as therapeutic agents against rheumatoid arthritis.     

Anti-cyclic citrullinated peptide antibodies in patients affected by HCV-related arthritis

Hepatitis C Virus (HCV) infection can induce immunological disorders with different clinical expressions such as arthritis, Sjogren Syndrome and various forms of vasculitis. Retrospectively, the prevalence of anti-Cyclic Citrullinated peptide antibodies (anti-CCP) in a group of patients affected by HCV-related arthritis with positivity for Rheumatoid Factor (RF) and the eventual correlations with RF and/or Anti-Nuclear Antibodies (ANA) and articular involvement were studied. Thirty patients with arthritis were selected from a population of 380 subjects affected by HCV infection. Each patient was evaluated by clinical examination (23 denoted poliarticular and 7 mono-oligoarticular involvement), by X-graphic aspects of joint involvement (8 patients presented joint erosions), by ANA, RF and anti-CCP positivity. Ten of the HCV-related arthritis patients (33.3 percent) presented positivity for anti-CCP, without significant correlation between such parameter and ANA, RF and articular involvement. Anti-CCP resulted positive in 4 out of the 8 patients with joint erosions, and only in 6 out of the 22 patients without joint erosions. Such frequencies analyzed by chi square resulted with no significant differences. Our patients presented an interesting prevalence of the positivity for anti-CCP. These data are cause to consider the specificity recently attributed to this parameter in the diagnosis of rheumatoid arthritis.     

Borrelia burgdorferi downregulates ICAM-1 on human synovial cells in vitro.

Lyme arthritis following infection with Borrelia burgdorferi (B. burgdorferi) is associated with the presence of bacteria in the joint, but the mechanism of persistent infection in the presence of specific antibodies and lymphocytes remains unknown. To investigate how an infection with B. burgdorferi might influence the local immune response in the joint, we examined the expression of cell adhesion molecules, human leucocyte antigens and inducible nitric oxide synthase (iNOS)-1 and -2 in human synovial cells after infection with B. burgdorferi in vitro. Synovial cells are known to influence the function of local immunologic effector cells and play a key role in the pannus formation of erosive arthritis. It has been shown previously that B. burgdorferi can persist in the cytosol of human synovial cells. The expression of the surface molecules ICAM-1, VCAM-1, HLA-class-I and -class-II and the cytosolic production of iNOS-1 and -2 in synovial cells was measured by flow cytometry for up to 5 days after infection with B. burgdorferi. A significant, lasting downregulation of surface ICAM-1 could be demonstrated on synovial cells, whereas no significant changes were seen in the expression of VCAM-1, HLA-class-I and -II, and of iNOS-1 and -2. To determine the biological significance of this downregulation an in vitro adhesion assay using peripheral blood mononuclear cells was developed. After infection with B. burgdorferi a significantly smaller number of mononuclear cells was adhering to the synovial cell monolayer. Adhesion of peripheral mononuclear cells was shown to be in part mediated by ICAM-1 by using a blocking mononuclear antibody against ICAM-1. Downregulation of ICAM-1 on synovial cells due to infection with B. burgdorferi might suppress the local immunosurveillance and might help the bacteria to persist in joint cells in vivo.     

Virus-neuron interactions in the mouse brain infected with Japanese encephalitis virus

The virus-host interactions between Japanese encephalitis (JE) virus and mouse brain neurons were analyzed by electron microscopy. JE virus replicated exclusively in the rough endoplasmic reticulum (RER) of neurons. In the early phase of infection, the perikaryon of infected neurons had relatively normal-looking lamellar RER whose cisternae showed focal dilations containing progeny virions and characteristic endoplasmic reticulum (ER) vesicles. The reticular RER, consisted of rows of ribosomes surrounding irregular-shaped, membrane-unbounded cisternae and resembled that observed in JE-virus-infected PC12 cells, were also seen adjacent to the lamellar RER. The appearance of the reticular RER indicated that RER morphogenesis occurred in infected neurons in association with the viral replication. The fine network of Golgi apparatus was extensively obliterated by fragmentation and dissolution of the Golgi membranes and their replacement by the electron-lucent material. As the infection progressed, the lamellar RER was increasingly replaced by the hypertrophic RER which had diffusely dilated cisternae containing multiple progeny virions and ER vesicles. The Golgi apparatus, at this stage, was seen as coarse, localized Golgi complexes near the hypertrophic RER. In the later phase of infection, RER of infected neurons showed a degenerative change, with the cystically dilated cisternae being filled with ER vesicles and virions. Small, localized Golgi complexes frequently showed vesiculation, vacuolation, and dispersion. The present study, therefore, indicated that during the viral replication the normal lamellar RER which synthesized neuronal secretory and membrane proteins was replaced by the hypertrophic RER which synthesized the viral proteins. The hypertrophic RER eventually degenerated into cystic RER whose cisternae were filled with viral products. The constant degenerative change which occurred in the Golgi apparatus during the viral replication suggested that some of the viral proteins transported from RER to the Golgi apparatus were harmful to the Golgi apparatus and that increasing damage to the Golgi apparatus during the viral replication played the principal role in the pathogenesis of JE-virus-infected neurons in the central nervous system.     

Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis.

Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.     

Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient

The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis. However treatment-related opportunistic infections and viral reactivations may still occur. We describe a case of varicella zoster virus (VZV) encephalitis due to the reactivation of latent VZV infection during a long therapy with the anti-tumor necrosis factor-alpha (TNF-alpha) drug Adalimumab. The low incidence of VZV encephalitis in patients treated with biological agents does not justify VZV serological screening in these subjects, but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications.     

Exacerbation of group B streptococcal sepsis and arthritis in diabetic mice

Group B streptococci (GBS) have been recognised as an ever-growing cause of serious invasive infections in non-pregnant adults, in particular in association with severe underlying diseases such as diabetes mellitus. In the present study we used mice rendered diabetic to gain further insights into host-pathogen interaction during induced GBS sepsis and septic arthritis. Type I diabetes was induced in adult CD-1 mice by low-dose streptozotocin treatment. Mice were then infected with different doses of GBS, and mortality, appearance of arthritis, growth of microorganisms in the organs and cytokine and chemokine profile were assessed in diabetic and control animals. The LD50 was significantly lower in diabetics than in controls, while both incidence and severity of arthritis were higher. A significantly higher number of microorganisms were recovered from the organs of diabetic mice than in controls. The worsening of sepsis and arthritis was associated with a significant increase in systemic and local production of IL-6, IL-1 beta, TNF-alpha, IL-10, macrophage inflammatory protein 1 alpha (MIP-1alpha), and MIP-2 and with a decrease in IFN-gamma production. Taken together, our results indicate an impaired host resistance to GBS infection in diabetics, likely due to a dysregulation of the cytokine network and prolonged local inflammatory response.     

Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD)

Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis.     

A comparison of complication rates in large and small inferior pedicle reduction mammaplasty

The main objective of this retrospective study was to determine whether the rates of complications are higher in large reductions (> or =1000 g per breast) as compared with smaller reductions (< or =999 g per breast) using the inferior pedicle technique. A retrospective chart review of 133 consecutive patients operated on between October of 2000 and March of 2002 was undertaken. Complication data were recorded and analyzed on a per-breast basis. Two hundred sixteen breasts had reductions of 999 g or less, whereas 50 breasts had reductions of 1000 g or more. The overall mean follow-up period was 152 days (range, 20 to 522 days). There were no statistically significant differences in the rates of nipple necrosis, hematoma formation, seroma, delayed healing, culture-positive wound infection, fat necrosis, cyst formation, nipple sensation, or hypertrophic scarring between the large and small reductions. However, the rate of wound dehiscence was significantly lower in the smaller reduction group. The rates of wound dehiscence and hypertrophic scarring were also significantly lower in patients who had received at least 5 days of postoperative antibiotics. A statistically significant difference was also reported for clinical wound infection (p < 0.0005). Body mass index had no statistically significant effect on the rate of nipple necrosis, hematoma formation, fat necrosis, cyst formation, nipple sensation, or hypertrophic scarring. However, body mass index had a statistically significant effect on delayed healing, wound dehiscence, and culture-positive wound infection. A higher mean body mass index predicted a delayed healing, wound dehiscence, and infection. The inferior pedicle technique is a safe method of breast reduction regardless of degree of parenchymal resection. However, the use of postoperative antibiotics for at least 5 days is recommended to reduce rates of wound dehiscence and improve postoperative scarring.     

缺氧复氧时肥大心肌细胞凋亡及其与能量代谢途径转换的关系

心肌细胞凋亡是心肌肥大向心力衰竭转化的重要机制,因此,抑制肥大心肌细胞凋亡可能是防治心力衰竭的有 效药物靶点之一。本研究以0．1μmol／L血管紧张素Ⅱ和1 μmol／L去甲肾上腺素刺激培养心肌细胞,复制心肌细胞肥大模 型,用三气孵箱培养。缺氧条件是95％N2和5％CO2,控制氧分压低于5 mmHg以下,8 h后常氧培养,液闪计数法测 定丙酮酸脱氢酶(pyruvate dehydrogenase,PDH)和肉碱脂酰转移酶-1(carnitine palmitoyltransferase 1,CPT-1)活性,糖氧化、 糖酵解、脂肪酸氧化率,以及细胞凋亡百分率,分析肥大心肌细胞能量代谢变化与细胞凋亡间的关系。结果如下:(1)与 常氧培养比较,缺氧8 h后,活化型丙酮酸脱氢酶(PDHa)和CPT-1活性均有显著下降,但复氧早期肥大心肌细胞PDHa活 性有轻度进一步降低(P>0．05),而CPT-1活性却较快恢复。(2)缺氧时,正常和肥大心肌细胞葡萄糖氧化代谢率均有降低[分 别下降(16±0．9)％、(48±1．1)％];复氧时,正常心肌细胞糖氧化代谢较快恢复,而肥大心肌细胞在复氧早期,糖氧化 率进一步降低,此后才逐渐恢复。(3)在缺氧时,肥大心肌细胞糖酵解率仅轻度下降,但在复氧后糖酵解率迅速升高,呈 爆发样达峰值后又逐渐恢复到缺氧前水平。(4)肥大心肌细胞在缺氧后脂肪酸代谢明显降低,但复氧后脂肪酸代谢呈爆发式 上升,并大大高于缺血前的代谢水平。(5)缺氧时肥大心肌细胞凋亡率即显著增加,在复氧早期细胞凋亡率继续大幅度上 升,此后逐渐减少。(6)预先用二氯乙酸处理肥大心肌细胞,可显著逆转缺氧复氧导致的细胞糖氧化受抑、糖酵解和脂肪 酸代谢活化,同时,抑制细胞凋亡的发生。上述结果提示,缺氧复氧后的肥大心肌细胞能量代谢途径转换是导致细胞凋 亡的重要原因。     

Ultrastructural study of the cat hypertrophic inferior olive following anterograde tracing, immunocytochemistry, and intracellular labeling

Contralateral cerebellectomy can induce hypertrophy of olivary neurons in cat. In the present study we examined the ultrastructure of the cat hypertrophic inferior olive following GABA-, dopamine- and serotonin-immunocytochemistry, anterograde tracing from the mesodiencephalic junction, and intracellular labeling with HRP. Compared to normal olivary neurons the hypertrophic cells showed larger cell bodies, more and longer somatic spines which were linked by gap junctions, and longer distal dendrites with relatively few spines. The hypertrophic olivary neurons received less GABAergic boutons on their dendrites but an equal percentage was apposed to their somata as compared to normal cells. Relatively many mesodiencephalic terminals, a similar serotoninergic, and a slightly increased dopaminergic input were found. The axon of one intracellularly labeled hypertrophic cell gave off recurrent collaterals bearing varicosities filled with vesicles. These results indicated that 1) hypertrophic olivary cells are affected by trophic factors not only at the cell body but also at the level of the somatic spines, dendrites, and axon, 2) the ratio of excitatory to inhibitory terminals is increased in the hypertrophic neuropil, whereas the monoaminergic input remains stationary, and 3) the electronic coupling between hypertrophic olivary neurons has shifted from a dendritic to a more somatic location due to a relatively high number of gap junctions between the somatic spines.     

Artritis séptica por Scedosporium apiospermum de lenta instauración tras infiltración periarticular

BackgroundFungal arthritis is usually of haematogenous origin, and mainly affects patients with impaired cellular immunity or users of intravenous drugs. The infection in immunocompetent patients is generally caused by direct inoculation of the microorganism through an invasive device. The experience of azole therapy in these patients is limited.Case reportWe report a case of arthritis caused by Scedosporium apiospermum characterized by its slow onset, lack of response to posaconazole and caspofungin, and its successful resolution after surgical debridement and treatment with voriconazole.ConclusionsTreatment with voriconazole and surgical debridement is an effective therapy for arthritis due to S. apiospermum.